TRPA1 mediates NADPH oxidase‐dependent cerebral artery dilation (1079.1)
Bibliographic record
Abstract
Activation of the Ca 2+ ‐permeable transient receptor potential (TRP) ankyrin (A) channel TRPA1 in the cerebral artery endothelium with electrophilic compounds induces dilation. Endogenous agonists for endothelial TRPA1 have not been reported. We hypothesized that H 2 O 2 is an endogenous agonist for TRPA1 in this tissue. H 2 O 2 can be generated by NADPH oxidase (NOX) activity via production of a O 2 ‐ intermediate or directly by NOX isoform NOX4. We find that activation of NOX with its substrate, NADPH, increases TRPA1 activity and induces dilation of pressurized cerebral arteries (80 mmHg) that is blocked by TRPA1 inhibitor HC‐030031 (HC) and H 2 O 2 degradation by catalase. In the presence of iron, H 2 O 2 is converted to highly reactive oxygen radicals, such as OH•, by the Fenton reaction. To distinguish between direct effects of H 2 O 2 vs. those of OH• or OH• metabolites we inhibited the Fenton reaction by chelating iron with deferoxamine. Deferoxamine attenuated NADPH‐induced TRPA1 activation and vasodilation, suggesting that OH• formation is required for NOX‐dependent TRPA1 activation. OH• peroxidizes membrane lipids yielding lipid peroxidation products (LPP). The LPP 4‐hydroxynonenal increased TRPA1 activity and induced cerebral artery dilation that was blocked by HC. Together, these data suggest that NOX‐dependent LPP generation activates TRPA1 in cerebral artery endothelial cells to induce vasodilation. Grant Funding Source : Supported by HL091905
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.001 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.004 | 0.002 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".